Design of 2-Aminobenzothiazole Derivatives Targeting Trypanosomatid PTR1 by a Multidisciplinary Fragment Hybridization Approach
Pteridine reductase 1 (PTR1) is a folate pathway enzyme essential for pathogenic trypanosomatids and a promising drug target for diseases such as sleeping sickness and leishmaniasis. Previous studies have shown that the 2-aminobenzothiazole moiety targets the PTR1 biopterin pocket, while 3,4-dichlorophenyl-containing compounds, such as <b>I</b> bind a different region of the <i>Trypanosoma brucei</i> PTR1 (<i>Tb</i>PTR1) pocket. This study combines both moieties via various linkers, creating two compound series screened in silico against <i>Tb</i>PTR1 and <i>Leishmania major</i> PTR1 (<i>Lm</i>PTR1). In the first series, five compounds were synthesized, and <b>1a</b> and <b>1b</b> emerged as potent <i>Tb</i>PTR1 inhibitors, with <b>1b</b> also being active against <i>Lm</i>PTR1 and moderately effective against <i>Leishmania infantum</i>. Furthermore, structure-activity relationship analysis, supported by quantum calculations and crystallography, revealed meta-halogenation to be more favorable than para, although single halogenation reduced antiparasite effects. Our fragment hybridization approach led to less toxic, more effective compounds than <b>I</b>.
Authors
- Joanna Panecka-Hofman (ORCID: https://orcid.org/0000-0003-4149-9090)
- Rebecca C. Wade (ORCID: https://orcid.org/0000-0001-5951-8670)
- Nuno Santarém (ORCID: https://orcid.org/0000-0003-4973-9933)
- Stefano Mangani (ORCID: https://orcid.org/0000-0003-4824-7478)
- Gesa Witt (ORCID: https://orcid.org/0000-0003-2344-706X)
- Rosaria Luciani (ORCID: https://orcid.org/0000-0003-1367-0217)
- Sheraz Gul (ORCID: https://orcid.org/0000-0003-2543-1643)
- Wiktoria Jedwabny (ORCID: https://orcid.org/0000-0002-1589-3097)
- Edyta Dyguda‐Kazimierowicz (ORCID: https://orcid.org/0000-0002-9154-5107)
- Ina Pöhner (ORCID: https://orcid.org/0000-0002-2801-8902)
- Pasquale Linciano (ORCID: https://orcid.org/0000-0003-0382-7479)
- Bernhard Ellinger (ORCID: https://orcid.org/0000-0001-5703-3901)
- Maria Paola Costi (ORCID: https://orcid.org/0000-0002-0443-5402)
- Stefania Ferrari (ORCID: https://orcid.org/0000-0003-1149-5953)
- Anabela Cordeiro‐da‐Silva (ORCID: https://orcid.org/0000-0003-2392-6087)
- Maria Kuzikov
- Cecilia Pozzi (ORCID: https://orcid.org/0000-0003-2574-3911)
- Giacomo Landi (ORCID: https://orcid.org/0000-0001-6332-166X)
- Daniele Aiello
Institutions
- University of Siena (IT)
- Wrocław University of Science and Technology (PL)
- University of Modena and Reggio Emilia (IT)
- University of Eastern Finland (FI)
- Heidelberg University (DE)
- University of Pavia (IT)
- Institute of Experimental Physics of the Slovak Academy of Sciences (SK)
- Faculty (United Kingdom) (GB)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- Finland University (FI)
- Institute of Biophysics (BG)
- Interuniversity Consortium for Magnetic Resonance (IT)
- DKFZ-ZMBH Alliance (DE)
- Institut de Biosciences et Biotechnologies (FR)
- Institut de Biologie Moléculaire et Cellulaire (FR)
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT)
- University of Warsaw (PL)
- Heidelberg Institute for Theoretical Studies (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-09-30
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01799
- Primary Topic
- Trypanosoma species research and implications
- Type
- article
- Field-Weighted Citation Impact
- 0.00